Human iPSC-derived fallopian tube organoids with BRCA1 mutation recapitulate early-stage carcinogenesis
| Autor: | Nur Yucer, Rodney Ahdoot, Michael J. Workman, Alexander H. Laperle, Maria S. Recouvreux, Kathleen Kurowski, Diana J. Naboulsi, Victoria Liang, Ying Qu, Jasmine T. Plummer, Simon A. Gayther, Sandra Orsulic, Beth Y. Karlan, Clive N. Svendsen |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
induced pluripotent stem cell
Carcinogenesis Nude Medical Physiology Induced Pluripotent Stem Cells Mice Nude Apoptosis General Biochemistry Genetics and Molecular Biology Mice Rare Diseases Clinical Research disease modeling Breast Cancer Tumor Cells Cultured 2.1 Biological and endogenous factors Animals Humans Aetiology Fallopian Tubes Germ-Line Mutation Cancer Cell Proliferation Ovarian Neoplasms fallopian tube Cultured Stem Cell Research - Induced Pluripotent Stem Cell - Human Stem Cell Research - Induced Pluripotent Stem Cell BRCA1 Protein Prevention Cell Differentiation Stem Cell Research Xenograft Model Antitumor Assays Tumor Cells Ovarian Cancer Organoids Good Health and Well Being Case-Control Studies Female Biochemistry and Cell Biology |
| Zdroj: | Cell reports, vol 37, iss 13 |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2021.110146 |
| Popis: | Germline pathogenic mutations in BReast CAncer (BRCA1) genes are thought to drive normal fallopian tube epithelial (FTE) cell transformation to high-grade serous ovarian cancer. No human models capture the sequence of events for disease initiation and progression. Here, we generate induced pluripotent stem cells (iPSCs) from healthy individuals and young ovarian cancer patients with germline pathogenic BRCA1 mutations (BRCA1mut). Following differentiation into FTE organoids, BRCA1mut lines exhibit cellular abnormalities consistent with neoplastic transformation compared to controls. BRCA1mut organoids show an increased production of cancer-specific proteins and survival following transplantation into mice. Organoids from women with the most aggressive ovarian cancer show the greatest pathology, indicating the potential value to predict clinical severity prior to disease onset. These human FTE organoids from BRCA1mut carriers provide a faithful physiological invitro model of FTE lesion generation and early carcinogenesis. This platform can be used for personalized mechanistic and drug screening studies. |
| Databáze: | OpenAIRE |
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